Early Tibial Vessel Recoil Following Treatment With the Bare Temporary Spur Stent System: Results From the DEEPER OUS Vessel Recoil Substudy.

PURPOSE: Vessel recoil is a common phenomenon occurring in the tibial vessels following balloon angioplasty. This study examined the occurrence and short-term impact of acute vessel recoil in a subset of patients treated with retrievable scaffold therapy (RST) via the Spur Peripheral Retrievable Scaffold System (Spur). METHODS: Patients with tibial disease underwent angiography immediately following RST, and then 15 minutes post-treatment. Vessel recoil was defined as a ≥10% decrease in lumen diameter after 15 minutes. Recoil was further analyzed by late lumen loss method, subsegmental late lumen loss method, and smallest segment to same segment method. Patient and vessel characteristics were evaluated. Functional recoil (acute vessel spasm), defined as no significant change in minimal lumen diameter (MLD) at baseline compared with 15 minutes post-treatment, was also evaluated. RESULTS: Of the 38 patients (40 lesions; 33 men [87%]; mean [SD] age 75.3 [8.2] years; 26 (68.4%) with diabetes mellitus); recoil was noted in 42.5% of vessels. Prior to treatment, 13 lesions (32.5%) were total occlusions, the mean lesion length was 64.7±30.4 mm, and 27.5% (11/40) were moderate or severely calcified. Mean treated lesion length was 97.8±39.6 mm. For lesions evaluable by duplex ultrasound, 86.7% of vessels (26/30) were patent at 6 months. There was no significant difference in patency between lesions with recoil and lesions without recoil (81.8% vs 89.5%); there was a trend toward patency in the non-recoil group. Two lesions had functional recoil (acute vessel spasm) and were patent at 6 months. There was no statistically significant correlation of recoil to comorbidities or lesion characteristics, including calcification, for which there was also no correlation to patency. CONCLUSION: Vessel recoil was noted in 42.5% of vessels treated with RST, whereas previous published rates with balloon angioplasty demonstrated vessel recoil up to 97%, suggesting that RST may impact vessel recoil. This exploratory study did not demonstrate a correlation between vessel recoil and patency at 6 months. CLINICAL IMPACT: Retrievable scaffold therapy may replace scoring devices and cutting devices for vessel preparation before definite (drug) therapy. Retrievable scaffold therapy supplements already established vessel preparation strategies in order to follow the concept of leaving nothing behaind. A temporary retrievable scaffold for changing vessel compliance and potentially releasing antiproliferative drugs represents a new interventional concept.

Safety and effectiveness of the Phoenix atherectomy device for endovascular treatment of common femoral and popliteal arteries: Results of the EN-MOBILE trial.

Background: This study aimed to assess the peri- and postprocedural outcomes of atherectomy-assisted endovascular treatment of the common femoral (CFA) and popliteal arteries. Methods: Phoenix atherectomy was used for the treatment of 73 and 53 de novo CFA and popliteal artery lesions, respectively, in 122 consecutive patients. Safety endpoints encompassed perforation and peripheral embolization. Postprocedural endpoints included freedom from clinically driven target lesion revascularization (CD-TLR) and clinical success (an improvement of ⩾ 2 Rutherford category [RC]). In addition, 531 patients treated for popliteal artery stenosis or occlusion without atherectomy were used as a comparator group. Results: Procedural success (residual stenosis < 30% after treatment) was 99.2%. The need for bail-out stenting was 2 (2.7%) and 3 (5.7%) in CFA and popliteal artery lesions, respectively. Only one (1.4%) embolization occurred in the CFA, which was treated by catheter aspiration. No perforations occurred. After 1.50 (IQR = 1.17-2.20) years, CD-TLR occurred in seven (9.2%) and six (14.6%) patients with CFA and popliteal artery lesions, respectively, whereas clinical success was achieved in 62 (91.2%) and 31 (75.6%), respectively. Patients treated with atherectomy and DCB in the popliteal artery after matching for baseline RC, lesion calcification, length, and the presence of chronic total occlusion, exhibited higher freedom from CD-TLR compared to the nondebulking group (HR = 3.1; 95% CI = 1.1-8.5, p = 0.03). Conclusion: Atherectomy can be used safely and is associated with low rates of bail-out stenting in CFA and popliteal arteries. CD-TLR and clinical success rates are clinically acceptable. In addition, for the popliteal artery, atherectomy combined with DCB demonstrates lower CD-TLR rates compared to a DCB alone strategy. (German Clinical Trials Register: DRKS00016708).

Novel Therapeutic Concepts for Complex Femoropopliteal Lesions Using the Jetstream Atherectomy System.

INTRODUCTION: The presence of severe arterial calcification is associated with less favorable outcomes in terms of procedural and clinical success as well as higher rates of major adverse limb events. Recent studies incorporating rotational atherectomy for effective preparation of severely calcified lesions demonstrate beneficial procedural outcomes by obtaining maximal luminal gain and improved long-term outcomes. METHODS: This prospective single-center, observational study includes patients with severely calcified femoropopliteal lesions with chronic limb ischemia Rutherford 1-5 between January 2017 and July 2019, who underwent atherectomy using the Jetstream Atherectomy system, followed by drug-coated balloon angioplasty. Lesion calcification was categorized by the Peripheral Arterial Calcium Scoring System (PACSS), whereas lesion complexity was classified by the Transatlantic Inter-Society Consensus (TASC). Safety and efficacy aspects in terms of vessel injury, thromboembolism, and clinical success were systematically analyzed up to 12 months of follow-up (FU). RESULTS: In 162 consecutive patients, 210 non-stented and 22 stented lesions were treated. Twelve (7.4%) patients received bail-out stenting. Mean lesion length was 24.2±4.8 cm; 51% were chronic total occlusions (mean occlusion length 18.2±5.1 cm). TASC C lesions were present in 38 patients (23.5%) and TASC D lesions in 124 patients (76.5%). The mean PACCS score was 3.3±0.9. Device success was achieved in 88%; procedural success was noted in 99% of the lesions. Embolic protection device was used in 11.7%. Perforation or dissection occurred in none of the cases. Asymptomatic peripheral embolization was noted in 10 patients (6.2%). Clinical FU at 12 months was available in 157 of 162 patients (96.9%). At 12 month FU, (1) mean Rutherford classification at baseline of 3.7±0.6 significantly dropped to 1.0±0.9 (p<0.05), (2) baseline mean anke-brachial index (ABI) of 0.4±0.1 significantly increased to 0.8±0.2 (p<0.05), (3) 92.6% were free from target lesion revascularization (TLR), (4) 95.1% were free from target vessel revascularization (TVR), and (5) binary restenosis measured by duplex occurred in 22 patients (13.6%). Multivariate analyses showed lesion length as predictive of stent placement (p=0.02), whereas both lesion length (p=0.006) and PACCS score (p=0.02) are predictive of clinical success. CONCLUSION: Rotational atherectomy in combination with drug-coated balloon (DCB) can be safely performed in long, calcified (non-) occlusive lesions with a relatively low rate of bail-out stenting and favorable clinical mid-term results. CLINICAL IMPACT: In this prospective, single arm study we demonstrated that combination treatment using rotational atherectomy and DCB is safe and effective in complex and calcified TASC C/D femoropopliteal lesions in patients with claudication or CLTI in a real-world clinical setting. Despite mean lesion length of >20cm and a relatively high rate of chronic total occlusions, the rate of bail-out stenting was surprisingly low (7.4%), whereas the rates of freedom from TLR and TVR were surprisingly high. Thus, our study may encourage vascular specialists to choose an endovascular -first approach even in such complex and calcified femoropopliteal lesions and occlusions in daily clinical practice.

Orbital Atherectomy Prior to Drug-Coated Balloon Angioplasty in Calcified Infrapopliteal Lesions: A Randomized, Multicenter Pilot Study.

PURPOSE: Optimal balloon angioplasty for infrapopliteal lesions is often limited by severe calcification, which has been associated with decreased procedural success and lower long-term patency. MATERIALS AND METHODS: This was a prospective, randomized, multicenter pilot trial that included adult subjects with calcified lesions located from the popliteal segment below the knee (BTK) joint to within 5 cm above the ankle with ≥70% diameter stenosis by angiography. Patients were randomized 1:1 to undergo orbital atherectomy (OA) with adjunctive drug-coated balloon (DCB) angioplasty versus plain balloon angioplasty (BA) and DCB angioplasty (control). The periprocedural and 12 month outcomes of both procedures were compared. RESULTS: Overall, 66 subjects (OA + DCB = 32 vs control = 34) were included in an intention to treat analysis. Baseline demographics and lesion characteristics were well-balanced. The mean lesion length was 101.3 mm (SD = 72.8 mm) and 78.8 (SD = 61.0 mm) in the OA + DCB and control groups, respectively, with almost all lesions having severe calcification per the Peripheral Academic Research Consortium (PARC) criteria. Chronic total occlusions (CTOs) were present in 43.8% and 35.3% of the patients in the OA + DCB and control groups, respectively. The technical success of OA + DCB versus DCB was 81.8% and 89.2%, respectively, with 3 slow flow/no reflow, 1 perforation, 1 severe dissection occurred in OA + DCB group, and one distal embolization occurred in the control group. The target lesion primary patency rate was numerically higher in the OA + DCB versus control group at 6 (88.2% vs 50.0%, p=0.065) and 12 month follow-up (88.2% vs 54.5%, p=0.076). The 12 month freedom from major adverse events, clinically-driven target lesion revascularization, major amputation, and all-cause mortality rates were similar between both groups. CONCLUSION: The results of the Orbital Vessel PreparaTIon to MaximIZe Dcb Efficacy in Calcified BTK (OPTIMIZE BTK) pilot study indicated that utilization of OA + DCB is safe for infrapopliteal disease. Further prospective adequately powered studies should investigate the potential benefit of combined OA + DCB for BTK lesions.

Safety, effectiveness and mid-term follow-up in 136 consecutive patients with moderate to severely calcified lesions undergoing phoenix atherectomy.

To investigate the safety and effectiveness of the Phoenix atherectomy device for the treatment of complex and calcified lesions in patients with peripheral artery disease (PAD). 136 consecutive all-comer patients with chronic PAD underwent Phoenix atherectomy. Safety in terms of vessel injury and embolism, efficacy and clinical success in terms of ≥ 1Rutherford class (RF) improvement during follow-up were systematically analyzed. Lesion calcification was categorized by the Peripheral Arterial Calcium Scoring System (PACSS), whereas lesion complexity was classified by the Transatlantic Inter-Society Consensus (TASC). 151 lesions were treated in 136 consecutive patients. Clinical follow-up was available at 10.3 ± 4.2 months in 132 (97%) patients. 55 patients (40%) had intermittent claudication, 16 (12%) rest pain and 65 (48%) had ischemic ulcerations (mean RF class = 4.2 ± 1.1). 15 (11%) patients had TASC B lesions, whereas the majority 72 (53%) and 49 (36%) exhibited TASC C and D lesions, respectively. Mean PACSS score was 3.3 ± 0.9. Mean lesion length was 106 ± 92 mm. Atherectomy was combined with drug-coated balloon (DCB) in 129 (95%) patients. Nine (6.6%) patients with infra-inguinal lesions received stents. Technical and procedural success were recorded in 102 (75%) and 135 (99%), respectively. Perforation was noticed in 2 (1%), whereas asymptomatic embolism occurred in 6 (4%) patients. Clinical success was present in 54 (100%) patients with claudication and in 65 of 78 (83%) patients with critical limb ischemia (CLI). Atherectomy in combination with DCB angioplasty can be safely performed in patients with complex, calcified peripheral lesions with a relatively low rate of bail-out stenting and promising clinical mid-term results.German Clinical Trials Register: DRKS00016708.

Critical role of RAGE and HMGB1 in inflammatory heart disease.

Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts proinflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). The involvement of the HMGB1-RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. Using the well-established model of TnI-induced experimental autoimmune myocarditis (EAM), we demonstrated that both local and systemic HMGB1 protein expression was elevated in wild-type (wt) mice after TnI immunization. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Together, our study highlights that HMGB1 and its main receptor, RAGE, appear to be crucial factors in the pathogenesis of TnI-induced EAM, because inhibition of HMGB1 and ablation of RAGE suppressed inflammation in the heart. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. Other receptors of HMGB1 such as Toll-like receptors (TLRs) may also be involved in disease pathogenesis. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy.

Short and long-term results after endovascular management of vascular complications during transfemoral aortic valve implantation.

Background Vascular injury and access site complications in the contemporary setting of transcatheter aortic valve implantation (TAVI) are known to be associated with increased mortality and morbidity. The aim of our study was to analyse the feasibility and safety of percutaneous treatment of such vascular complications using a stent graft. Methods Between January 2010 and April 2013, 36 TAVI patients developed severe access site complications and underwent subsequent interventional treatment with a covered stent. Acute treatment success was confirmed by angiography immediately after the implantation of the stent graft, with clinical long-term patency follow-up being assessed by duplex ultrasound. Results Of the 36 patients evaluated, percutaneous treatment of the acute access site bleeding was successful in 35 patients (97%), with one patient requiring surgical intervention due to insufficient haemostasis after stent graft implantation. A subset of 5 patients underwent successful ipsilateral stent graft implantation, either because crossover sheath placement was not feasible (n = 1), or intentionally with an even sheathless approach in an effort to reduce vessel injury (n = 4). After a mean follow-up of 22 ± 8 months, stent graft patency was confirmed by duplex ultrasound in 13 patients with an additional 5 patients reporting to be free from symptoms and claudication. Thirteen patients died within the first 24 months after the procedure, however, none was due to access vessel complications. Five patients were lost for follow-up. Conclusions Our data confirm that endovascular treatment of access site complications related to TAVI is feasible, safe and efficacious, resulting in long-term vascular patency.

SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy.

Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy. Heterotopic heart transplants from H-2bm12 to B6 mice and aortic transplants from Balb/c to B6 were performed. Mice were treated with NOX-A12. Control animals received a nonfunctional Spiegelmer (revNOX-A12). Samples were retrieved at different time points and analysed by histology, RT-PCR and proliferation assay. Blockade of SDF-1 caused a significant decrease in neointima formation as measured by intima/media ratio (1.0 ± 0.1 vs. 1.8 ± 0.1, P < 0.001 AoTx; 0.35 ± 0.05 vs. 1.13 ± 0.27, P < 0.05 HTx). In vitro treatment of primary vascular smooth muscle cells with NOX-A12 showed a significant reduction in proliferation (0.42 ± 0.04 vs. 0.24 ± 0.03, P < 0.05). TGF-ß, TNF-α and IL-6 levels were significantly reduced under SDF-1 inhibition (3.42 ± 0.37 vs. 1.67 ± 0.33, P < 0.05; 2.18 ± 0.37 vs. 1.0 ± 0.39, P < 0.05; 2.18 ± 0.26 vs. 1.6 ± 0.1, P < 0.05). SDF-1/CXCR4/CXCR7 plays a critical role in the development of chronic allograft vasculopathy (CAV). Therefore, pharmacological inhibition of SDF-1 with NOX-A12 may represent a therapeutic option to ameliorate chronic rejection changes.

Short-term akt activation in cardiac muscle cells improves contractile function in failing hearts.

Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a phosphatidylinositol 3-kinase-dependent manner. By using a conditional transgenic system in which Akt signaling can be turned on or off in the adult heart, we previously showed that short-term Akt activation induces a physiological form of cardiac hypertrophy with enhanced coronary angiogenesis and maintained contractility. Here we tested the hypothesis that induction of physiological hypertrophy by short-term Akt activation might improve contractile function in failing hearts. When Akt signaling transiently was activated in murine hearts with impaired contractility, induced by pressure overload or doxorubicin treatment, contractile dysfunction was attenuated in both cases. Importantly, improvement of contractility was observed before the development of cardiac hypertrophy, indicating that Akt activation improves contractile function independently of its growth-promoting effects. To gain mechanistic insights into Akt-mediated positive inotropic effects, transcriptional profiles in the heart were determined in a pressure overload-induced heart failure model. Biological network analysis of differentially expressed transcripts revealed significant alterations in the expression of genes associated with cell death, and these alterations were reversed by short-term Akt activation. Thus, short-term Akt activation improves contractile function in failing hearts. This beneficial effect of Akt on contractility is hypertrophy-independent and may be mediated in part by inhibition of cell death associated with heart failure.

S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-κB signaling.

The extracellular heterodimeric protein S100A8/A9 activates the innate immune system through activation of the receptor of advanced glycation end products (RAGE) and Toll-like receptors. As activation of RAGE has recently been associated with sustained myocardial inflammation and heart failure (HF) we studied the role of S100A8/A9 in the development of post-ischemic HF. Hypoxia led to sustained induction of S100A8/A9 accompanied by increased nuclear factor (NF-)κB binding activity and increased expression of pro-inflammatory cytokines in cardiac fibroblasts and macrophages. Knockdown of either S100A8/A9 or RAGE rescued the induction of pro-inflammatory cytokines and NF-κB activation after hypoxia. In a murine model of post-ischemic HF both cardiac RNA and protein levels of S100A8/A9 were elevated as soon as 30 min after hypoxia with sustained activation up to 28 days after ischemic injury. Treatment with recombinant S100A8/A9 resulted in reduced cardiac performance following ischemia/reperfusion. Chimera experiments after bone marrow transplantation demonstrated the importance of RAGE expression on immune cells for their recruitment to the injured myocardium aggravating post-ischemic heart failure. Signaling studies in isolated ventricles indicated that MAP kinases JNK, ERK1/2 as well as NF-κB mediate signals downstream of S100A8/A9-RAGE in post-ischemic heart failure. Interestingly, cardiac performance was not affected by administration of S100A8/A9 in RAGE(-/-)-mice, which demonstrated significantly improved cardiac recovery compared to WT-mice. Our study provides evidence that sustained activation of S100A8/A9 critically contributes to the development of post-ischemic HF driving the progressive course of HF through activation of RAGE.

Phoenix atherectomy for patients with peripheral artery disease.

BACKGROUND: Endovascular atherectomy enables minimally invasive plaque removal in peripheral artery disease (PAD). AIMS: We aimed to evaluate the safety and the long-term effectiveness of the Phoenix atherectomy for the treatment of complex and calcified lesions in PAD patients. METHODS: Consecutive all-comer patients with PAD underwent the Phoenix atherectomy. Device safety in terms of perforation and distal embolisation were evaluated. Lesion calcifications were categorised by the Peripheral Arterial Calcium Scoring System (PACSS) and lesion complexity was assessed by the Transatlantic Inter-Society Consensus (TASC). Clinically driven target lesion revascularisation (TLR) was assessed. RESULTS: A total of 558 lesions were treated in 402 consecutive patients. Clinical follow-up was available at 15.7±10.2 months for 365 (91%) patients. Of 402 patients, 135 (33.6%) had claudication, 37 (9.2%) had ischaemic rest pain and 230 (57%) exhibited ischaemic ulcerations. Lesions were mostly identified in the femoropopliteal segments (55%), followed by below-the-knee (BTK) segments (32%). Complex TASC C/D lesions and moderate to severe calcifications (PACSS score ≥2) were present in 331 (82%) and 323 (80%) patients, respectively. The mean lesion length was 20.6±14.3 cm. Five (1%) perforations and 10 (2%) asymptomatic embolisations occurred. Bail-out stenting was performed in 4%, 16% and 3% of patients with common femoral artery, femoropopliteal and BTK lesions, respectively. During follow-up, 5 (3.9%) patients with claudication and 52 (21.9%) patients with critical limb-threatening ischaemia (CLTI) died (hazard ratio [HR] 3.7; p<0.001). Freedom from TLR was 87.5% (112 of 128) in patients with claudication and 82.3% (195 of 237) in patients with CLTI, respectively (HR 1.8; p=0.03). CONCLUSIONS: The Phoenix atherectomy can be safely performed in patients with complex lesions with a relatively low rate of bail-out stenting and clinically acceptable TLR rates. GERMAN CLINICAL TRIALS REGISTER: DRKS00016708.

Deletion of bone marrow-derived receptor for advanced glycation end products inhibits atherosclerotic plaque progression.

BACKGROUND: The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the inflammatory response in atherosclerosis. We sought to determine the role of bone marrow-derived RAGE in different stages of atherosclerotic development in apolipoprotein E-deficient mice (apoE(-/-)). METHODS: Seven- and 23-week-old apoE(-/-) mice (n = 40) were lethally irradiated and given bone marrow from RAGE null (RAGE(-/-)/apoE(-/-)) or RAGE-bearing (RAGE(+/+)/apoE(-/-)) mice to apoE(-/-) mice to generate double knockout bone marrow chimera (RAGE(-/-)/apoE(-/-bmc) and RAGE(+/+)/apoE(-/-bmc)-, respectively). After 16 weeks on a standard chow diet, mice were sacrificed and atherosclerotic lesion formation was evaluated. RESULTS: Plaques in the aortic root of the young mice showed no significant difference in maximum plaque size (217,470 ± 17,480 µm(2) for the RAGE(-/-) /apoE(-/-bmc) mice compared to 244,764 ± 45,840 µm(2)), whereas lesions in the brachiocephalic arteries of the older RAGE(-/-)/apoE(-/-bmc) mice had significantly smaller lesions (94,049 ± 13,0844 µm(2) vs. 145,570 ± 11,488 µm(2), P < 0.05) as well as reduced average necrotic core area (48,600 ± 9220 µm(2) compared to 89,502 ± 10,032 µm(2), P < 0.05) when compared to RAGE(+/+)/apoE(-/-bmc) mice. Reduced plaque size and more stable plaque morphology was associated with significant reduced expression of VCAM-1, ICAM-1 and MCP-1. Accumulation of the RAGE ligand HMGB-1 was also significantly reduced within the lesions of RAGE(-/-)/apoE(-/-bmc) mice. CONCLUSIONS: This study demonstrates that bone marrow-derived RAGE is an important factor in the progression of atherosclerotic plaques.

HMGB1: the missing link between diabetes mellitus and heart failure.

Diabetes mellitus (DM) is a major independent risk factor for cardiovascular disease, but also leads to cardiomyopathy. However, the etiology of the cardiac disease is unknown. Therefore, the aim of this study was to identify molecular mechanisms underlying diabetic heart disease. High glucose treatment of isolated cardiac fibroblasts, macrophages and cardiomyocytes led to a sustained induction of HMGB1 on the RNA and protein level followed by increased NF-κB binding activity with consecutively sustained TNF-α and IL-6 expression. Short interference (si) RNA knock-down for HMGB1 and RAGE in vitro confirmed the importance of this axis in diabetes-driven chronic inflammation. In a murine model of post-myocardial infarction remodeling in type 1 diabetes, cardiac HMGB1 expression was significantly elevated both on RNA and protein level paralleled by increased expression of pro-inflammatory cytokines up to 10 weeks. HMGB1-specific blockage via box A treatment significantly reduced post-myocardial infarction remodeling and markers of tissue damage in vivo. The protective effects of box A indicated an involvement of the mitogen-activated protein-kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the transcription factor nuclear factor-kappaB. Interestingly, remodeling and tissue damage were not affected by administration of box A in RAGE(-/-) mice. In conclusion, HMGB1 plays a major role in DM and post-I/R remodeling by binding to RAGE, resulting in activation of sustained pro-inflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a therapeutic strategy to reduce post-ischemic remodeling in DM.

The role of HMGB1/RAGE in inflammatory cardiomyopathy.

Heart failure is an increasingly prevalent disorder with considerable morbidity and mortality. Although many causal mechanisms such as inherited cardiomyopathies, ischemic cardiomyopathy, or muscular overload are easily identified in clinical practice, the events that determine the progression of cardiac injury to heart failure and adverse ventricular remodeling are still unclear. Yet there is compelling evidence that inflammatory mechanisms contribute to the progression of heart failure. High-mobility group box-1 (HMGB1) is a newly recognized potent innate "danger signal" that is released by necrotic cells and by activated immune cells. HMGB1 signals via the receptor for advanced glycation end-product (RAGE) and members of the toll-like receptor (TLR) family. We have demonstrated an important role for HMGB1 and RAGE in the pathogenesis of early- and late-phase complications following ischemia/reperfusion (I/R) injury of the heart. In addition, enhanced postmyocardial infarction remodeling in type 1 diabetes mellitus was partially mediated by HMGB1 activation. We propose that the interaction of HMGB1 and RAGE is a key component initiating and sustaining the inflammatory response in inflammatory cardiomyopathy eventually leading to heart failure. Thus HMGB1-antagonizing gene therapy represents a new therapeutic strategy.

Early assessment of infarct size and prediction of functional recovery by quantitative myocardial blush grade in patients with acute coronary syndromes treated according to current guidelines.

PURPOSE: To determine whether quantification of myocardial blush grade (MBG) during cardiac catheterization can aid the determination of follow-up left ventricular (LV)-function in patients with ST-elevation and non-ST-elevation myocardial infarction (STEMI and NSTEMI). METHODS: We prospectively examined patients with first STEMI (n = 46) and NSTEMI (n = 49). ECG-gated angiographic series were used to quantify MBG by analyzing the time course of contrast agent intensity rise. Hereby, the parameter G(max)/T(max) was calculated, derived from the plateau of grey-level intensity (G(max)), divided by the time-to-peak intensity (T(max)). Cardiac magnetic resonance imaging (CMR) deemed as the standard reference for the estimation of infarct size, transmurality and of the LV-function at 6 months of follow-up. RESULTS: Cut-off values of G(max)/T(max)=5.7/sec and 3.8/sec, respectively, yielded similar accuracy as infarct transmurality for the prediction of follow-up ejection fraction >55% (AUC = 0.86 for STEMI and AUC = 0.90 for NSTEMI, by G(max)/T(max) and AUC = 0.85 for STEMI and AUC = 0.89 for NSTEMI, by infarct transmurality, respectively, P = NS). Both clearly surpassed the predictive value of visual MBG (AUC = 0.69 for STEMI and AUC = 0.68 for NSTEMI, P < 0.05). CONCLUSION: G(max)/T(max) is an easy to acquire but highly valuable surrogate parameter for infarct size, which yields equally high accuracy with infarct transmurality and favorably compares with visually assessed blush grades for the prediction of follow-up LV-function in patients with acute ischemic syndromes.

High-mobility group box-1 in ischemia-reperfusion injury of the heart.

BACKGROUND: High-mobility group box-1 (HMGB1) is a nuclear factor released by necrotic cells and by activated immune cells. HMGB1 signals via members of the toll-like receptor family and the receptor for advanced glycation end products (RAGE). Although HMGB1 has been implicated in ischemia/reperfusion (I/R) injury of the liver and lung, its role in I/R injury of the heart remains unclear. METHODS AND RESULTS: Here, we demonstrate that HMGB1 acts as an early mediator of inflammation and organ damage in I/R injury of the heart. HMGB1 levels were already elevated 30 minutes after hypoxia in vitro and in ischemic injury of the heart in vivo. Treatment of mice with recombinant HMGB1 worsened I/R injury, whereas treatment with HMGB1 box A significantly reduced infarct size and markers of tissue damage. In addition, HMGB1 inhibition with recombinant HMGB1 box A suggested an involvement of the mitogen-activated protein kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the nuclear transcription factor nuclear factor-kappaB in I/R injury. Interestingly, infarct size and markers of tissue damage were not affected by administration of recombinant HMGB1 or HMGB1 antagonists in RAGE(-/-) mice, which demonstrated significantly reduced damage in reperfused hearts compared with wild-type mice. Coincubation studies using recombinant HMGB1 in vitro induced an inflammatory response in isolated macrophages from wild-type mice but not in macrophages from RAGE(-/-) mice. CONCLUSIONS: HMGB1 plays a major role in the early event of I/R injury by binding to RAGE, resulting in the activation of proinflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a novel therapeutic strategy in I/R injury.

The evolving role of drug-coated balloons for the treatment of complex femoropopliteal lesions.

Conventional therapies for transcatheter treatment of patients with infrainguinal obstructive disease remain compromised by high restenosis rates. Drug-coated balloons (DCB) offer a novel therapeutic alternative targeting the source of neo-intimal hyperplasia, without the need for a permanent endovascular scaffold and their inherent limitations. A systematic research of the medical databases (Pubmed) has been conducted for this up-to-date review. Key words, such as "drug-coated balloons" (DCB), "drug-eluting balloon," "in-stent-restenosis" (ISR), "de-novo stenosis," "plain old angioplasty," "atherectomy," "debulking," "superficial femoral artery," "popliteal artery," "above/below the knee," and "peripheral artery disease" have been used for literature search. Furthermore, data from reviews, original contributions, randomized controlled studies, observational studies, registries and single center experiences have been considered. Overall, an increasing level of evidence supports the use of DCB for the treatment of long, complex, heavily calcified femoropopliteal non-occlusive and occlusive lesions, including failure after BM stent implantation due to ISR. However, more studies will be necessary to investigate the long-term effects of DCB-treatment in these real-world lesions.